Behavioral and Molecular Biomarkers in Translational Animal Models for Neuropsychiatric Disorders

Sarnyai, Zoltán; Alsaif, Murtada; Bahn, Sabine; Ernst, Agnes; Guest, Paul C.; Hradetzky, Eva; Kluge, W; Stelzhammer, Viktoria; Wesseling, Hendrik

doi:10.1016/b978-0-12-387718-5.00008-0

Cited by 30 publications

(15 citation statements)

References 216 publications

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“…Molecular findings have been used to show similarities between humans and rodents supporting the view that behaviour alterations are linked to molecular changes 190,199 . Given the reported pool of findings it seems unlikely that a difference in any single molecule would be enough to assign a given animal model to a distinct psychiatric disorder.…”

Section: Discussionmentioning

confidence: 78%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50 Keywords: Translational research, neuropsychiatry, genetic, neurodevelopment, animal model, schizophrenia. ResumoSintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.Gottschalk MG, et al. / Rev Psiq Clín. 2013;40(1):41-50

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Section: Discussionmentioning

confidence: 78%

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Gottschalk

Sarnyai

Guest

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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“…Hence, it is felt that future models of SCZ should be focused on behavioural endophenotypes and more importantly molecular alterations, as we gain more understanding of the genetic and neurodevelopmental causes (Powell and Miyakawa, 2006;Stewart and Kalueff, 2015). In particular given the failures of current medications in treatment of negative and cognitive symptoms of SCZ, preclinical models for different symptom clusters are likely to play an increasingly important role in new pharmacological approaches (Keefe et al, 2007;Sarnyai et al, 2011;Tomasik et al, 2014Tomasik et al, , 2015. Our results provide evidence that different models can represent functional aspects of SCZ more closely than others, however future research should aim to introduce proteomic information of different putative SCZ animal models, most notably dopaminergic manipulations using direct and indirect dopamine agonists which have previously shown to induce behavioural phenotypes associated with positive and negative symptoms of SCZ such as hyperactivity, persisting prepulse inhibition abnormalities and attention deficit (Jones et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Proteomic systems evaluation of the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology

Cox

Gottschalk

Wesseling

et al. 2016

Schizophrenia Research

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Pharmacological and genetic rodent models of schizophrenia play an important role in the drug discovery pipeline, but quantifying the molecular similarity of such models with the underlying human pathophysiology has proved difficult. We developed a novel systems biology methodology for the direct comparison of anterior prefrontal cortex tissue from four established glutamatergic rodent models and schizophrenia patients, enabling the evaluation of which model displays the greatest similarity to schizophrenia across different pathophysiological characteristics of the disease. Liquid chromatography coupled tandem mass spectrometry (LC-MS) proteomic profiling was applied comparing healthy and "disease state" in human post-mortem samples and rodent brain tissue samples derived from models based on acute and chronic phencyclidine (PCP) treatment, ketamine treatment or NMDA receptor knockdown. Protein-protein interaction networks were constructed from significant abundance changes and enrichment analyses enabled the identification of five functional domains of the disease such as "development and differentiation", which were represented across all four rodent models and were thus subsequently used for cross-species comparison. Kernel-based machine learning techniques quantified that the chronic PCP model represented schizophrenia brain changes most closely for four of these functional domains. This is the first study aiming to quantify which rodent model recapitulates the neuropathological features of schizophrenia most closely, providing an indication of face validity as well as potential guidance in the refinement of construct and predictive validity. The methodology and findings presented here support recent efforts to overcome translational hurdles of preclinical psychiatric research by associating functional dimensions of behaviour with distinct biological processes.

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“…The underlying causes are still not fully understood, resulting in only partial success with early diagnosis and no novel drug entities discovered over the past decade. The latter effect results from the lack of preclinical models, which accurately reflect the underlying pathologies (Sarnyai et al, 2011). In particular, modeling SCZ in animals is made difficult by the poor translation of behavioral readouts to the diverse, nonspecific symptoms of the human disease.…”

Section: Introductionmentioning

confidence: 99%

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

Wesseling

Chan

Tsang

et al. 2013

Neuropsychopharmacol

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Current schizophrenia (SCZ) treatments fail to treat the broad range of manifestations associated with this devastating disorder. Thus, new translational models that reproduce the core pathological features are urgently needed to facilitate novel drug discovery efforts. Here, we report findings from the first comprehensive label-free liquid-mass spectrometry proteomic-and proton nuclear magnetic resonance-based metabonomic profiling of the rat frontal cortex after chronic phencyclidine (PCP) intervention, which induces SCZ-like symptoms. The findings were compared with results from a proteomic profiling of post-mortem prefrontal cortex from SCZ patients and with relevant findings in the literature. Through this approach, we identified proteomic alterations in glutamate-mediated Ca 2 þ signaling (Ca 2 þ /calmodulin-dependent protein kinase II, PPP3CA, and VISL1), mitochondrial function (GOT2 and PKLR), and cytoskeletal remodeling (ARP3). Metabonomic profiling revealed changes in the levels of glutamate, glutamine, glycine, pyruvate, and the Ca 2 þ regulator taurine. Effects on similar pathways were also identified in the prefrontal cortex tissue from human SCZ subjects. The discovery of similar but not identical proteomic and metabonomic alterations in the chronic PCP rat model and human brain indicates that this model recapitulates only some of the molecular alterations of the disease. This knowledge may be helpful in understanding mechanisms underlying psychosis, which, in turn, can facilitate improved therapy and drug discovery for SCZ and other psychiatric diseases. Most importantly, these molecular findings suggest that the combined use of multiple models may be required for more effective translation to studies of human SCZ.

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Behavioral and Molecular Biomarkers in Translational Animal Models for Neuropsychiatric Disorders

Cited by 30 publications

References 216 publications

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

Proteomic systems evaluation of the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology

A Combined Metabonomic and Proteomic Approach Identifies Frontal Cortex Changes in a Chronic Phencyclidine Rat Model in Relation to Human Schizophrenia Brain Pathology

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